Each year large numbers of children undergo surgery involving exposure to general anesthesia. Whether such exposure increases a child's neurodevelopmental risk has never been established. Studies in animal models provide compelling evidence that commonly used agents (e.g., isoflurane, midazolam, nitrous oxide) enhance neuronal cell death in the immature brain, in some studies at doses lower than those required to achieve a surgical plane of anesthesia. The clinical implications of these data are controversial, however, because no prospective study has evaluated neurodevelopment in children after exposure to anesthetic agents in infancy. This application seeks funding for U.S. participation in an international, prospective, multi-site, randomized, controlled, equivalence trial comparing children's neurodevelopment following receipt of general or regional awake anesthesia. A total of 220 infants who undergo inguinal herniorrhaphy, a common surgery that can be performed using either form of anesthesia, will be enrolled at 9 sites in the USA over a 27-month period. Because a total of 24 patients have been enrolled during our pilot phase, an additional 196 patients will be enrolled during this project. An additional 440 infants will be enrolled at sites in Australia and the United Kingdom, for a total enrollment of 660. Funding has been obtained for the non-USA sites. The primary hypothesis is that neurodevelopmental outcomes at 2 years of age are equivalent in children who received general anesthesia or regional awake anesthesia. The primary endpoint will be the Cognitive score on the Bayley Scales of Infant and Toddler Development-3rd edition (BSID-III). Secondary endpoints include the Language and Motor Composite scores on the BSID-III, scores on the MacArthur-Bates Communicative Development Inventory, and neurologic status. The secondary hypothesis is that apnea rates in the first 12 post-operative hours are equivalent in the treatment groups. Multiple linear or logistic regression analysis, adjusting for potential confounders, will be used to estimate treatment group differences. The primary hypothesis of equivalence in Cognitive score at 2-years of age will be accepted if the 2-sided 95% confidence interval of the adjusted treatment group difference in means lies within -5 and +5 points. In light of the widespread use of general anesthesia in infant surgery, the results are likely to have substantial public health implications.